Elsevier

Brain and Development

Volume 27, Issue 3, April 2005, Pages 201-206
Brain and Development

Review article
Aicardi–Goutières syndrome

https://doi.org/10.1016/j.braindev.2003.12.011Get rights and content

Abstract

Aicardi–Goutières syndrome is a familial progressive early onset encephalopathy with basal ganglia calcifications, chronic CSF lymphocytosis and high level of interferon-α in CSF. Cutaneous necrotic lesions and the neuropathological aspect of microangiopathy and microinfarctions suggest a vascular process in relation to elevated interferon-α. A genetic defect in the regulation of its synthesis may be the causal factor of the disorder.

Introduction

The Aicardi–Goutières syndrome (AGS) was first described in 1984 by these authors who reported on eight infants from five families suffering from an early onset familial encephalopathy with chronic CSF lymphocytosis and basal ganglia calcifications, mimicking an intrauterine infectious process but with negative TORCH investigations [1]. In the first family observed, a misleading genetic counselling had been given to the consanguineous parents after the birth of an affected child erroneously thought suffering from a viral foetopathy and a second child similarly affected was born. Clinically, the patients showed bilateral spasticity, dystonia, ocular jerks, acquired progressive microcephaly with a rapid course towards profound deterioration and death. In addition to basal ganglia calcifications, computerized tomography (CT) scan showed diffuse and progressive brain atrophy and deep white matter hypodensities. The authors suggested a probable genetic condition with autosomal recessive inheritance. They identified in the literature nine previously reported possibly similar cases of unclassified leukodystrophy with calcifications [2], [3], [4], [5]. Following the publication of similar cases [6], [7], [8], [9], the disorder was listed under the eponym AGS by McKusick as autosomal recessive 22,575 [10]. In 1988, Pierre Lebon [11] impressed by the chronic CSF lymphocytosis and the cerebral calcifications had the idea to study interferon-α (inf-α) previously shown to be elevated in congenital rubella and in acquired herpetic encephalitis. Inf-α was detected in the CSF from five of the six patients tested and was not detected in 44 control infants with various neurological syndromes of non-infectious nature. Since this study, elevated CSF inf-α is considered as the best marker for the syndrome and systematically looked for in patients in whom this diagnosis is suspected. It is currently considered as a cue to the diagnosis [12]. After their initial publication of eight children [1], the authors reviewed 19 additional patients [13] and numerous other cases have been reported so far [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. This list included the familial cases of Kumar [22] who are reported as distinct from AGS. These cases, in my opinion, raise a nosological problem that is discussed below. An important series of 21 Italian cases has been published recently [26]. To date, 74 cases have been reported throughout the world. AGS is present, at least in Europe, in North Africa, in North and South America, in Japan and possibly in Pakistan.

Section snippets

Clinical manifestations

The clinical presentation is a very early progressive encephalopathy. Onset is before 4 months of age in most patients, in some within the first week. Weight and head circumference at birth are within the normal range, but occasional cases with congenital microcephaly are on record [7], [9], [13], [19], [24]. One patient showed deceleration of head growth in utero suggestive of a prenatal onset [14]. Others without microcephaly at onset presented with a reduction of the cranial circumference

Imaging features

Calcification of the basal ganglia is the hallmark of the syndrome and a major diagnostic clue. Calcifications were detected in all the 27 patients observed by Goutières and Aicardi [13]. They are better detected by CT scan which is the first choice imaging investigation rather than magnetic resonance imaging (MRI). They affect the putamina, which are mostly involved, the pallidum, the thalami and in some patients, the dentate nuclei and the subcortical areas. Their aspect varies from

CSF findings

Chronic CSF lymphocytosis is the third main characteristic of AGS. In my experience, all CSF samples contained eight or more lymphocytes per cubic millimeter in the first 12 months of life (between 10 and 50 in most patients). Lymphocytosis varied at first examination from 260 mm−3 at the age of 3 days in one patient to 6 mm−3 at 19 months in another, with normal subset of lymphocytes. It decreases with age but persisted beyond the age of 2 years in two patients [13]. One patient of McEntagart

Other laboratory data investigations

They give normal results for blood calcium, phosphorus, amino acid and organic acid chromatographies, immunoglobulins and lysosomal enzymes activities. Virological research in blood and CSF for TORCH, varicella, adenovirus, human T-cell leukemia virus type I and II, human immunodeficiency virus type I and II are negative [13]. Anemia with microcytosis [22], increased levels of hepatic transaminases and thrombocytopenia at birth [13], [26] have been exceptionally noticed. Brain auditory evoked

Genetics

AGS is inherited as autosomal recessive. A genome-wide linkage analysis of 23 children from 13 families has demonstrated linkage to chromosome 3p21 in a proportion of the families but not in all [32]. This suggests the existence of at least one additional disease locus. This hypothetical genetic heterogeneity may possibly correspond to clinical heterogeneity [33].

Differential diagnosis and nosological issues

The diagnosis includes a large number of disorders as the symptoms are not characteristic. Intrauterine infections due to rubella, herpes virus, cytomegalovirus or toxoplasmosis are frequently misleadingly suspected because of the lymphocytosis and calcifications; they are the first diagnoses to be excluded as erroneous genetic counselling might ensue. Cockayne syndrome (CS), a familial leukodystrophy with striato-cerebellar calcifications caused by defective repair of transcriptionally active

Physiopathology

The origin of the disorder is still unknown but the main lesions appear to be a calcifiing vasculitis that affects both brain and systemic vessels. This vasculitis is similar to that observed in mice receiving astrocyte-targeted inf-α which develop a progressive encephalopathy with basal ganglia calcifications similar to the neuropathological lesions in AGS [40]. In addition, cutaneous vascular lesions bearing similarities to the chilblains observed in AGS, in MICS and in Cree ‘encephalitis’

Conclusions

There exist a group of disorders with similar clinical features and that share a number of biological features. In these cases in which adequate investigations have been performed, AGS was the first of these conditons and remain the best studied so far. Although its mechanisms are not fully understood, the role of the high levels of inf-α as a probable cause of diffuse vasculitis seems established. One likely hypothesis is that the basic mechanism could be a dysregulation of production and

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